chr2-201085526-G-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_002491.3(NDUFB3):c.208G>T(p.Gly70Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,612,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00016 ( 0 hom. )
Consequence
NDUFB3
NM_002491.3 stop_gained
NM_002491.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 8.47
Genes affected
NDUFB3 (HGNC:7698): (NADH:ubiquinone oxidoreductase subunit B3) This gene encodes an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which is the first enzyme in the electron transport chain of mitochondria. This protein localizes to the inner membrane of the mitochondrion as a single-pass membrane protein. Mutations in this gene contribute to mitochondrial complex 1 deficiency. Alternative splicing results in multiple transcript variants encoding the same protein. Humans have multiple pseudogenes of this gene. [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.3 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-201085526-G-T is Pathogenic according to our data. Variant chr2-201085526-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39836.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1, Likely_pathogenic=1}. Variant chr2-201085526-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFB3 | NM_002491.3 | c.208G>T | p.Gly70Ter | stop_gained | 3/3 | ENST00000237889.9 | |
NDUFB3 | NM_001257102.2 | c.208G>T | p.Gly70Ter | stop_gained | 4/4 | ||
NDUFB3 | XM_011511230.4 | c.208G>T | p.Gly70Ter | stop_gained | 4/4 | ||
NDUFB3 | XM_047444488.1 | c.208G>T | p.Gly70Ter | stop_gained | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFB3 | ENST00000237889.9 | c.208G>T | p.Gly70Ter | stop_gained | 3/3 | 1 | NM_002491.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 151756Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000116 AC: 29AN: 251020Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135664
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GnomAD4 exome AF: 0.000160 AC: 233AN: 1460588Hom.: 0 Cov.: 32 AF XY: 0.000158 AC XY: 115AN XY: 726622
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GnomAD4 genome AF: 0.000158 AC: 24AN: 151874Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13AN XY: 74182
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:3Uncertain:1
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The NDUFB3 p.Gly70* variant was identified as a compound heterozygous variant in individuals with mitochondrial complex I deficiency; functional studies in fibroblasts from this patient demonstrated low complex I activity (Haack_2012_PMID:22499348). The variant was identified in dbSNP (ID: rs200800978) and ClinVar (classified as likely pathogenic by GeneDx and as pathogenic by Ambry Genetics). The variant was identified in control databases in 31 of 282238 chromosomes at a frequency of 0.0001098 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 24 of 128702 chromosomes (freq: 0.000187), Latino in 5 of 35410 chromosomes (freq: 0.000141), Other in 1 of 7204 chromosomes (freq: 0.000139) and South Asian in 1 of 30608 chromosomes (freq: 0.000033), but was not observed in the African, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The c.208G>T variant leads to a premature stop codon at position 70, which is predicted to lead to a truncated or absent protein and loss of function in homozygous individuals. Loss of function variants in the NDUFB3 gene are an established mechanism of disease for mitochondrial complex I deficiency and are the type of variant expected to cause the disorder when found in homozygous or compound heterozygous individuals. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 14, 2022 | This sequence change creates a premature translational stop signal (p.Gly70*) in the NDUFB3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the NDUFB3 protein. This variant is present in population databases (rs200800978, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 22499348, 26795593). ClinVar contains an entry for this variant (Variation ID: 39836). Studies have shown that this premature translational stop signal alters NDUFB3 gene expression (PMID: 22499348). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 02, 2019 | DNA sequence analysis of the NDUFB3 gene demonstrated a sequence change, c.208G>T, which results in the creation of a premature stop codon at amino acid position 70, p.Gly70*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated NDUFB3 protein with potentially abnormal function. This sequence change has previously been described in a patient with isolated complex I deficiency along with another missense variant in this gene, and functional studies were performed to demonstrate pathogenicity (Haack et al., 2012). The phenotypic presentation included mitochondrial encephalopathy, mitochondrial myopathy, muscular hypotonia, developmental delay and lactic acidosis. These collective evidences indicate that this sequence change is likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 01, 2022 | Published functional studies demonstrate a damaging effect, specifically expression of NDUFB3 cDNA with either the p.W22R or p.G70X variants failed to rescue the complex I deficiency in patient fibroblasts (Haack et al., 2012); Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 33233646, 26795593, 31589614, 22499348) - |
Mitochondrial complex 1 deficiency, nuclear type 25 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 26, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2012 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 10, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at